In lab tests using mice with breast cancer, researchers found that the drug combination suppressed the cancer stem cells thought to drive tumor progression.

"We discovered that metformin selectively kills cancer stem cells. Very few compounds do that," said Kevin Struhl, lead researcher of a paper appearing in the Sept. 14 online early edition of Cancer Research.

Stem cells are resistant to chemotherapy, and scientists had hoped to find a compound that kills them. "The basic idea in the stem cell hypothesis is that standard chemotherapy can kill the cancer cells that make up the bulk of the tumor, but it's not getting the stem cells, so they re-grow and the tumor comes back. That's a classic pattern," said Struhl, a professor of biological chemistry and molecular pharmacology at Harvard Medical School.

That metformin is a known compound adds to the good news. "The exciting thing was that they found an old and relatively safe compound and showed that it had a property that was selectively toxic to cancer stem cells," said Dr. Jonathan Chernoff, deputy scientific director at Fox Chase Cancer Center in Philadelphia. "That's new."

Metformin, which is marketed under the brand names Glucophage, Riomet, Fortamet, Glumetza, Obimet, Dianben and Diabex, is an agent that makes the body more sensitive to insulin. Over decades, millions of people have taken it.

"It's known that diabetics who take metformin have a much lower cancer incidence than diabetics who don't, so there has been a hint that the drug might be useful," said Struhl.

One recent study found that metformin may lower a diabetic patient's risk of developing pancreatic cancer by as much as 60 percent.

What was unclear was whether metformin helps diabetics deal better with their blood sugar levels and insulin sensitivity or whether it affects the cancer itself. The results of this study point strongly to the latter.

Mice in this study that simultaneously received metformin and doxorubicin, a common chemotherapy agent, showed reductions in tumor size in four types of breast cancer, as well as longer remission times.

On its own, metformin, which was given in lower doses than normal for diabetics, did not have such a striking effect, indicating that the two treatments in combination are key.

Scientists hope that the metformin-chemo combination will result in a need for less chemo, thereby reducing painful side effects.

"Basically the [current] chemo dose is set up to give you as much as you can possibly tolerate on the grounds that the more you kill, the better it is, but likely you're overdoing to do that," Struhl said. "If you could cut [chemotherapy] in half, for example, and use metformin, you might get equally good clinical results and cut side effects."

Researchers also hope that the metformin protocol could have similar synergistic effects in other types of cancers.

Although it's always wise to be cautious when interpreting studies done in mice, "some of the cells they were testing were actually of human origin, so even though they were tested for tumorigenicity in mice, it still has some relevance," Chernoff said.

Researchers are planning clinical trials, which will be the "ultimate test," Struhl said.

Researchers may also start looking at other drugs for similar effects. If other known drugs with good safety profiles prove effective, "that would be an incredible thing," Chernoff said.

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